Weekly Sepsis Research Analysis
This week’s sepsis literature is dominated by high-impact clinical trials and mechanistic discoveries that directly alter hemodynamic targets and nominate new immunomodulatory targets. A multicenter RCT (OPTPRESS) shows higher MAP targets (80–85 mmHg) increase 90‑day mortality in older patients with septic shock, changing practice for MAP goals. Mechanistic work identifies regulatory nodes in inflammatory cell death and platelet-driven immunothrombosis (RING1→GSDMD and platelet NLRP6→TRIM21–TAB1
Summary
This week’s sepsis literature is dominated by high-impact clinical trials and mechanistic discoveries that directly alter hemodynamic targets and nominate new immunomodulatory targets. A multicenter RCT (OPTPRESS) shows higher MAP targets (80–85 mmHg) increase 90‑day mortality in older patients with septic shock, changing practice for MAP goals. Mechanistic work identifies regulatory nodes in inflammatory cell death and platelet-driven immunothrombosis (RING1→GSDMD and platelet NLRP6→TRIM21–TAB1–NF‑κB), opening druggable pathways. Across the week, advanced causal-inference methods and trajectory/biomarker modeling also featured as tools to personalize therapy.
Selected Articles
1. Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): a multicentre, pragmatic, open-label, randomised controlled trial.
OPTPRESS randomized 518 patients ≥65 years with septic shock to MAP targets 80–85 mmHg versus 65–70 mmHg. The trial was stopped early for harm: 90‑day mortality was higher in the high‑MAP group (39.3% vs 28.6%; risk difference 10.7%, 95% CI 2.6–18.9). Renal replacement therapy–free days were fewer with the high‑MAP strategy and no subgroup (including chronic hypertension) benefited.
Impact: Provides high-level randomized evidence that higher MAP targets harm older septic shock patients, directly informing and likely changing guideline-recommended MAP goals.
Clinical Implications: Avoid targeting MAP 80–85 mmHg in elderly septic shock patients; preferentially use standard targets (≈65–70 mmHg) and monitor for renal support needs if higher vasopressor exposure is considered.
Key Findings
- Trial stopped early for harm; 90‑day mortality higher with MAP 80–85 mmHg (39.3%) vs 65–70 mmHg (28.6%).
- Risk difference 10.7% (95% CI 2.6–18.9).
- No subgroup, including chronic hypertensives, derived benefit from higher MAP; fewer RRT-free days in high‑MAP group.
2. Platelet NLRP6 protects against microvascular thrombosis in sepsis.
Using platelet‑specific knockout mice and CLP sepsis models, the study shows platelet NLRP6 limits microvascular thrombosis, platelet activation, platelet–neutrophil interactions, and NET formation via promoting TRIM21–mediated K48 polyubiquitination and degradation of TAB1, thereby restraining NF‑κB signaling. NF‑κB inhibition rescued the prothrombotic phenotype and improved survival; sepsis plasma triggered the same pathway ex vivo in human platelets.
Impact: Identifies a platelet‑intrinsic pathway controlling immunothrombosis with translational potential to reduce organ injury in sepsis without global immune suppression.
Clinical Implications: Targeting platelet NLRP6 signaling or downstream TAB1–NF‑κB interactions may reduce microvascular thrombosis and organ injury in sepsis; human translational studies and safety evaluations (bleeding risk) are needed.
Key Findings
- Platelet NLRP6 deletion increased mortality and microvascular thrombosis in CLP sepsis models.
- NLRP6 promotes TRIM21–TAB1 interaction → K48 polyubiquitination and degradation of TAB1, suppressing platelet NF‑κB signaling.
- NF‑κB inhibition reversed the prothrombotic effects and improved survival; sepsis plasma triggers NLRP6/TRIM21–mediated TAB1 degradation in human platelets ex vivo.
3. RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection.
This mechanistic study shows RING1 is an E3 ligase that promotes K48‑linked ubiquitination of GSDMD (at K51/K168), driving proteasomal degradation and limiting pyroptosis. Ring1 deficiency increased mortality and bacterial burden in Salmonella and worsened LPS‑induced sepsis; pharmacologic or genetic RING1 inhibition enhanced GSDMD levels and pyroptotic cell death, nominating RING1–GSDMD as a druggable axis.
Impact: Uncovers a central ubiquitin‑mediated brake on pyroptosis with broad implications for immunomodulatory therapies in sepsis and infectious disease.
Clinical Implications: Modulating RING1 activity could rebalance host defense versus immunopathology in sepsis; next steps include preclinical safety evaluation of RING1 modulators and stratifying patients with dysregulated pyroptosis.
Key Findings
- RING1 promotes K48‑linked ubiquitination of GSDMD at K51 and K168, leading to proteasomal degradation and suppression of pyroptosis.
- Ring1 knockout mice show increased mortality and bacterial burden in Salmonella infection and exacerbated LPS‑induced sepsis.
- Inhibition of RING1 increases GSDMD levels and pyroptotic cell death, positioning RING1 as a therapeutic target.